Growth factor gene transfer to articular chondrocytes may be capable of augmenting cell-based approaches to articular cartilage repair. Currently available data is insufficient to enable translation into clinical use. The purpose of this proposal is to help close the gap between present mechanistic knowledge and therapeutic application. We will focus on three related specific aims. Aim 1: Define a potentially therapeutic set of growth factor genes for articular cartilage repair by determining how interactions among selected growth factors regulate articular chondrocyte function. Hypothesis 1: IGF-I, FGF-2, BMP-2, and BMP-7, when employed for articular chondrcyte gene transfer, interact to differentially regulate the expression of genes that influence chondrocyte reparative functions. Aim 2: Determine whether genetic and tissue engineering methods, when applied to articular chondrocytes, are interdependent. Hypothesis 2: Chemically distinct biomaterials, including alginate, collagen, and hyaluronic acid-based gels, differentially modulate the effects of growth factor gene transfer. Aim 3: Determine whether transfer of an optimized set of growth factor genes coupled with an optimized biomaterial can generate durable repair in a large animal model of cartilage loss. Hypothesis 3: Optimal repair of articular cartilage lesions requires a modulation of cell proliferation and matrix synthesis. Articular chondrocytes treated by gene transfer with selected combinations of growth factors and delivered in a selected hydrogel differentially promote repair of intrachondral articular cartilage defects in the equine knee. The demonstration that interactions between these genetic engineering and tissue engineering technologies promote repair by articular chondrocytes would lend insight into the mechanisms that regulate cell-based therapies and provide a key step in the translation of these therapies to human articular cartilage diseases.